Osteoarthritis (OA) is a significant health problem causing diminished quality of life for patients and a financial stress on the health care system as the population ages. Early diagnosis and development of new treatments is hampered by the inability to diagnose the earliest stages of OA, when treatment would be most effective. Fibrillation of type II collagen (CII) is one of the earliest signs of cartilage damage in OA, and the ability to detect this early degeneration of CII would have a major impact on OA diagnosis and the development of new therapeutic drugs. Our long-term goal is to develop non-invasive imaging technology for use in the clinical evaluation of arthritis. The objective of this application is to establish proof-of-concept that second harmonic generation (SHG) can be used to image CII directly in articular joints. The central hypothesis of this application is that CII will be the primary source of SHG signal emitted by the articular joint, and that SHG imaging will be capable of distinguishing between native intact CII and CII in the early stages of degeneration. The rationale is that the validation of SHG imaging of CII in mouse models of OA will be a major step toward the translation of this technology into the clinic. This hypothesis will be tested and the objective of this application accomplished by pursuing two specific aims: (1)Validate the use of SHG for imaging CII and identify the molecular components of cartilage that contribute to the SHG emission, and (2) Demonstrate the use of SHG for live non-invasive imaging of CII in mouse knee joints. The proposed project is innovative because it makes use of the inherent crystalline structure of CII to visualize this molecule in its native or diseased state within the joint. We expect this pilot project to establish the potential of SHG as a new method for joint imaging. The results will be significant because they will advance the field of non- invasive imaging and establish SHG as an important new tool with the capacity to detect minor changes in CII that cannot be detected by other methods currently in use in the clinical setting.